- Email: [email protected]
Cisplatin, methotrexate, and 5-fluorouracil combination chemotherapy for advanced ovarian cancer
GYNECOLOGK
ONCOLOGY
20, 290-297 (1985)
Cisplatin, Methotrexate, and 5-Fluorouracil Combination Chemotherapy for Advanced Ovarian Cancer P. F. CONTE,* M. R. SERTOLI,* M. BRUZZONE,” A. RUBAGOTTI,” R. ROSSO,* G. BENTIVOGLIO,? A. cONlo,t AND G. PESCETTOt” *Istituto
Nazionale
per la Ricerca ml Cancro, Divisione di Oncologia Medica 1, and t Clinica Ostetrica Ginecologica dell’Universita, Genoa, Italy
Received November 29, 1983 A combination chemotherapy including cisplatin, 25 mgim* on Days I ,8; methotrexate, 30 mg/m’ on Day 1; and Muorouracil, 600 mg/m’ on Day 1 has been evaluated in 28 previously untreated and 10 pretreated patients with advanced ovarian cancer after debulking surgery when feasible. The pathological response rates (complete + partial responses) were 69.2 and 50% in untreated and pretreated patients, respectively. Overall 24-month survival and progression-free survival (PFS) are 19.2 and 10.9%, respectively. A significant difference in survival and PFS is evident between patients with less and more than 2 cm residual disease and between responders (CR + PR) versus nonresponders. No renal toxicity was induced and no cycles had to be delayed because of hemathologic toxicity. 0 1985 Academic
Press, Inc.
INTRODUCTION
Ovarian cancer is becoming one of the major causes of death due to gynecologic malignancy in western countries [l]. The death rate is high because early diagnosis is incidental and most cases are diagnosed when abdominal spread has already occurred [2]. However, ovarian cancer is responsive to chemotherapy: monochemotherapy with alkylating agents is likely to give a 20-30% objective response, though complete responses are quite rare [3,4]. Combination chemotherapy has produced increases both in the response rate and percentage of complete responses [5]. In recent years a new agent, cis-diamminedichloroplatinum has shown high activity in ovarian cancer [6] and combination chemotherapy including CDDP has further raised the response rate to 70-90% [7-111. Furthermore the association of aggressive debulking surgery followed by platinum-based combination chemotherapy has substantially increased the percentage of surgically documented complete remissions. Some of these complete responders may be cured. Most of the published results have been obtained by combining CDDP with alkylating agents and/or Adriamycin. Unfortunately this combination is heavily myelosuppressive or car’ To whom correspondence should be addressed at: Clinica Ostetrica Ginecologica Universita, Viale Benedetto XV, 10, 16132, Genoa, Italy. 290 0090~8258/85 $1.50 Copyright All rights
0 1985 by Academic Press. Inc. of reproduction in any form reserved
POLICHEMOTHERAPY
IN
ADVANCED
OVARIAN
CANCER
291
diotoxic and not always feasible in elderly ovarian cancer patients who have already undergone aggressive surgery. In an attempt to reduce the toxicity and treat even older patients while maintaining efficacy, we have utilized a new combination chemotherapy regimen where moderate doses of CDDP are administered in two divided doses in association with two antimetabolites: methotrexate and S-fluorouracil. The two antimetabolites were chosen for their efficacy in monochemotherapy and their lack of leukemogenic activity. The aims of our study were (i) to assess the effectiveness of P, methotrexate (M), and 5-fluorouracil (F) in stage III-IV ovarian cancer patients following optimal debulking surgery (residual disease d 2 cm); (ii) to verify the feasibility of debulking surgery after six courses of PMF in those cases where, at diagnosis, optimal surgical resection had not been possible (residual disease > 2 cm, biopsy only); (iii) to evaluate the effectiveness and the toxicity of PMF in a consecutive series of patients with no age criteria exclusion. We present here our final results at 24 months follow-up. PATIENTS AND METHODS
The treatment plan was the following: after initial surgery, six PMF courses (P, 25 mg/m*, Days 1 and 8; M, 30 mg/m’, Day 1; F, 600 mg/m*, Day 1, iv, q 28) were administered. The patients who had an optimal debulking underwent a surgical second look after six courses of PMF. The patients with bulky residual disease (RD) after primary surgery (RD > 2 cm) underwent a second debulking procedure after six courses of PMF, if a clinical response had been achieved. Clinical response was evaluated by physical examination and serial echographies at 3-month intervals. After second surgery six further PMF courses were administered if a pathological complete response (PCR) was not documented. A few cases underwent a third-look surgery. The patients who progressed were submitted to second-line chemotherapy. Definition of response (clinical complete response, CCR; pathological complete response, PCR; clinical partial response, CPR; pathological partial response, PPR; and progression, P) was established according to ECOG criteria [12]. The eligibility criteria were histologically proven diagnosis of epithelial ovarian cancer FIG0 stage 111or IV; normal renal function; normal hemocytometry; no other malignancy. No age limit was set; the patients’ characteristics and surgical operation are summarized in Tables 1 and 2. Since June 1981, 38 consecutive patients entered the study: 10 relapsing patients pretreated with chemotherapy (4 with CDDP) and 28 untreated patients (of these 7 underwent optimal debulking surgery, RD s 2 cm; 19 suboptimal surgery with RD > 2 cm; 2 died after the first course of treatment due to extensive disease, and are considered for survival only, not for response). Survival time was measured in months from the first day of chemotherapy to the date of death or to time of last follow-up; survival time was analyzed using the life-table methods of Kaplan and Meier [13]. The statistical significance was tested by the log-rank test [14].
292
CONTE
ET AL.
TABLE 1 PATIENTS’
CHARACTERISTICS
38 38 36
Entered in study Evaluated for survival Evaluated for response Age Median Range Pretreatment Previously treated Untreated
52 37-84 10 28
AND PRIMARY SURGERY
Primary surgery” Complete surgery Incomplete surgery Biopsy only FIG0 stage” III IV Residual disease before CT” RD < 2 cm RD > 2 cm
15 1 12 19 9 8 20
’ Untreated patients only.
RESULTS In the 19 untreated patients with RD > 2 cm, a clinical response rate of 57.9% was observed (26.3% CCR, 31.6% CPR). In the 10 pretreated patients 4 CCR and 1 CPR were obtained (Table 3). Eighteen untreated patients (7 with RD G 2 cm, 11 with RD > 2 cm who experienced a CCR or CPR) underwent secondlook surgery. The following pathological responses were observed (Table 4): 5 PCR (3 patients with RD G 2 cm, 2 patients with RD > 2 cm) and 13 PPR (4 patients with RD G 2 cm, 9 patients RD > 2 cm). Of the 13 PPR, 3 showed microscopic disease; only 5 PPR patients could be further resected with resulting RD 6 2 cm. All the 13 PPR patients underwent six more cycles of PMF: 4 achieved a CCR and were submitted to third look, but pathological residual disease was still present. Among pretreated patients two-fourths CR were confirmed at second look; interestingly one of these patients had been previously pretreated with a CCDPcontaining regimen. The survival and the progression-free survival (PFS) for the entire group of patients and for the patients with more or less than 2 cm RD are reported in Figs. 1 and 2, respectively. The median survival for the entire group is 13.5 TABLE 2 TUMOR HISTOLOGY
Histology Serous Mutinous Endometrioid Undifferentiated Not specified G, G G Not specified y Untreated patients.
AND GRADINGS
No. patients 9 4 2 2 11 3 5 5 15
POLICHEMOTHERAPY
IN
ADVANCED
OVARIAN
293
CANCER
TABLE 3 CLINICAL RESFQNSEIN EVALUABLE PATIENTS’ AT 3 MONTHS
No. patients
OR%
CCR%
CPR%
P%
19
57.9 50.0
26.3 40.0
31.6 10.0
42.1 50.0
PCRW
PPRW
P%”
19.2 10.5 42.9 30.0
50.0 47.4 57.1 20.0
30.8 42. I 50.0
Untreated patients Pretreated patients
10
” Residual disease > 2 cm.
TABLE 4 SURGICAL RESFQNSEAT SECOND-LOOK SURGERY
No. secondlook surgery
No. patients Total untreated >2 cm RD ~2 cm RD Pretreated
18 11 7
26 19
7 10
2
’ Percentages refer to the initial number of patients (column 1).
.-._.-.-.- .-.-f \\
cweru,, PtS (581 residual
',L.-.-.-.-.-. __
((
disease cc
s 2Cm (9)
.-.-.~.-.-
> *cm (29)
------
\ \
;.---,
101
I--.----ntrtb~fron
the
is start
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72lthe trcrtnlcnt
FIG. 1. Survival. Median survival for all patients is 13.5 months, median survival for patients with initial residual disease more than 2 cm is 10.5 months, median survival for patients with initial disease less than 2 cm has not yet been reached. The difference in survival between the two patients population is significant (P < 0.05).
294
CONTE ET AL.
over011 P’(S (381 reslduol disease s2cm (9) .-.-.-.-.z2cm (29) -----(( N
1
5
months
fa from
the
start
15 of the
20 treatment
25
FIG. 2. Progression-free survival. Median time to progression for all patients is 9 months, median time to progression for patients with initial residual disease more than 2 cm is 8.3 months, median time to progression for patients with initial residual disease less than 2 cm has not yet been reached at 24 months. The difference between the two patients population is significant (P < 0.025).
months (10.5 months for the patients with more than 2 cm RD; while it has not yet been reached at 24 months for the patients with less than 2 cm RD). At 24 months overall survival is 19.2% and probability of PFS 10.9% (66.6% for patients with RD 6 2 cm, 0% for the patients with RD greater than 2 cm). Survival and PFS according to the type of pathological response are reported in Figs. 3 and 4. For the seven patients who achieved a PCR the 2-year survival and PFS rates are 50 and 60%, respectively and are significantly better p < 0.00025) than those observed in nonresponders. No grade 2-3 ECOG renal or hemathological toxicity was recorded during the chemotherapeutic cycles. DISCUSSION Combination chemotherapy with platinum, alkylating agents, and/or Adriamycin is a highly effective induction regimen in advanced ovarian carcinoma and clinical complete remission rate of 60-80% can be achieved [7-l I]. However, these regimens often show gastrointestinal, renal, and bone marrow toxicities and many older patients cannot withstand these treatments [9,11]. Therefore we have tried to evaluate the efficacy of a more tolerable regimen, PMF. Our results confirm that a high response rate can be achieved: 57.9% OR in patients with clinically evaluable RD; 42.9% PCR in patients with optimally resected disease. Moreover, despite the inclusion of elderly patients in the study,
POLICHEMOTHERAPY
IN
ADVANCED
OVARIAN
10 _--15’. .8 ---;a--------__----_ i
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1,
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295
CANCER
PCR (8)
~
PPn 115)
------
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(131
-.
'1
80
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'\
9:,
7?
-5
.3
ki \
I
,
a0 \ ,l-.
\
-boo~~ ~~~~~~*~ of
the
treatment
3. Survival according to response. Actuarial survival at 24 months for complete responders is 50%. No progressor survived beyond 14 months. The difference in survival between responders (CR + PR) and nonresponders (P) is significant (P < 0.00025). FIG.
roogh 9
%T
-8 -__-_ch_- 15’ ‘\ i \I I**---* i :\
PCR (8)
~
PPR (15)
------
4
-5--
months
l-0
from
the
start
f5
of
the
20 treatment
25
4. Progression-free survival according to response. A significant difference is evident between responders (CR + PR) and nonresponders (P) (P < 0.00025) while no significant difference is detectable between CR vs PR (P < 0.25). FIG.
296
CONTE ET AL.
no grade 2 ECOG renal or myelotoxicity was observed. A 50% response rate has been obtained even in pretreated patients with two PCR documented at second look. The importance of second-look laparotomy to prove the type of response to chemotherapy is confirmed by our study. Fewer than 50% of the patients in CCR are free of disease at surgery. Achievement of a PCR is important for survival; about 60% of PCR patients will be disease free at 24 months. The probability of reaching a PCR is related to the extent of RD after initial surgery; 42.9% of patients with RD s 2 cm will obtain a PCR versus 10.5% of patients with bulky RD. Though the role of second-look surgery may be essential in the identification of those patients pathologically free of disease who can stop treatment, its therapeutic value still remains to be determined. In our series 13 patients were in PPR at second look; 3 patients had microscopic disease only, and 5 patients were further resected with resulting RD s 2 cm. All these patients were treated with further six PMF courses but no PCR was documented in the 4 patients who underwent a third-look laparotomy. In conclusion our results confirm that (i) ovarian cancer patients can be treated safely and effectively with combination chemotherapy including moderate doses of CDDP; (ii) achievement of a PCR depends on the extent of RD after initial surgery; (iii) patients who achieve a PCR have a longer survival; and (iv) secondlook surgery is essential for accurate evaluation of the extent of response to treatment, but its therapeutic value remains to be demonstrated. REFERENCES 1. Silverberg, E. Cancer statistics, Cancer 31, 13-28 (1981). 2. Aure, J. C., Hoeg, K., and Kolstad, P. Clinical and histological studies of ovarian carcinoma. Long term follow-up of 990 cases, Obstet. Gynecol. 37, l-9 (1977). 3. Smith, J. P., and Rutledge, F. Chemotherapy in the treatment of cancer of the ovary, Amer. J. Obstet. Gynecol. 107, 691-703 (1970). 4. Young, R. C. Chemotherapy of ovarian cancer: Past and present, Semin. Oncol. 2, 267-276 (1975). 5. Young, R. C., Chabner, B. A., Hubbard, S. P., Fisher, R. I., Bender, R. A., Anderson, T., Simon, R. M., Canellos, G. P., and De Vita, V. T. Advanced ovarian carcinoma. A prospective clinical trial of Melphalan (L-PAM) versus combination chemotherapy, N. Engl. J. Med. 299, 1261-1266 (1978). 6. Wiltshaw, E., and Can, B. Cis-plantinum (II) diammino-dichloride clinical experience of the Royal Marsden and Institute of Cancer Research, Recent Results Cancer Res. 48, 178-182 (1978). 7. Ehrlich, C. E., Einhorn, L., Williams, S. D., and Morgan, J. Chemotherapy for stage III-IV epithelial ovarian cancer with cis-dichlorodiammine-platinum (II), adriamycin and cyclophosphamide: A preliminary report, Cancer Treat. Rep. 63, 281-288 (1979). 8. Barker, G. H., and Wiltshaw, E. Randomized trial comparing low-dose cis-platin and chlorambucil with low-dose cisplatin, chlorambucil and doxorubicin in advanced ovarian carcinoma, Lancer 1, 747-750 (1981). 9. Cohen, C. J., Goldberg, J. D., Holland, J. F., Bruckner, H. W., Deppe, G., Gusberg, S. B., Wallach, R. C., Kabakow, B., and Rodin, J. Improved therapy with cisplatin regimens for patients with ovarian carcinoma (FIG0 stages III and IV) as measured by surgical end staging (second-look operation), Amer. J. Obstet. Gynecol. 145, 955-967 (1983).
POLICHEMOTHERAPY
IN ADVANCED
OVARIAN
CANCER
297
10. Williams, C. J., Stevenson, K. E., Buchanan, R. B., and Whitehouse, J. M. A. Advanced ovarian carcinoma: A pilot study of cis-dichlorodiammineplatinum (II) in combination with adriamycin and cyclophosphamide in previously untreated patients and as a single agent in previously treated patients, Cancer Treat. Rep. 63, 1745-1753 (1979). 11. Edwards, C. L., Herson, L., Gershenson, D. M., Coperland, L. J., and Wharton, J. T. A prospective randomized clinical trial of melphalan and cis-platinum versus hexamethylmelamine, adriamycin and cyclophosphamide in advanced ovarian cancer, Gynccol. Oncol. 1.5, 261-277 (1983). 12. Oken, M. M., Creech, R. H., Tormey, D. C., and Horton, J. Toxicity and response criteria of the Eastern Cooperative Oncology Group, Amer. J. Clin. Oncol. 5, 649-655 (1982). 13. Kaplan, E. L., and Meier, P. Non parametric estimation from incomplete observation, /. Amer. Std. Assoc. 53, 457-481 (1958).
14. Peto, R., Pike, M. C., Armitage, P., Breslow, N. E., Cox, D. R., Howard, S. V., Mantel, N., MacPherson, K., Peto, J., and Smith, P. G. Design and analysis of randomized clinical trials requiring prolonged observation of each patient, &it. J. Cancer 34, 385-612 (1976); 35, 1-39 (1977).
ONCOLOGY
20, 290-297 (1985)
Cisplatin, Methotrexate, and 5-Fluorouracil Combination Chemotherapy for Advanced Ovarian Cancer P. F. CONTE,* M. R. SERTOLI,* M. BRUZZONE,” A. RUBAGOTTI,” R. ROSSO,* G. BENTIVOGLIO,? A. cONlo,t AND G. PESCETTOt” *Istituto
Nazionale
per la Ricerca ml Cancro, Divisione di Oncologia Medica 1, and t Clinica Ostetrica Ginecologica dell’Universita, Genoa, Italy
Received November 29, 1983 A combination chemotherapy including cisplatin, 25 mgim* on Days I ,8; methotrexate, 30 mg/m’ on Day 1; and Muorouracil, 600 mg/m’ on Day 1 has been evaluated in 28 previously untreated and 10 pretreated patients with advanced ovarian cancer after debulking surgery when feasible. The pathological response rates (complete + partial responses) were 69.2 and 50% in untreated and pretreated patients, respectively. Overall 24-month survival and progression-free survival (PFS) are 19.2 and 10.9%, respectively. A significant difference in survival and PFS is evident between patients with less and more than 2 cm residual disease and between responders (CR + PR) versus nonresponders. No renal toxicity was induced and no cycles had to be delayed because of hemathologic toxicity. 0 1985 Academic
Press, Inc.
INTRODUCTION
Ovarian cancer is becoming one of the major causes of death due to gynecologic malignancy in western countries [l]. The death rate is high because early diagnosis is incidental and most cases are diagnosed when abdominal spread has already occurred [2]. However, ovarian cancer is responsive to chemotherapy: monochemotherapy with alkylating agents is likely to give a 20-30% objective response, though complete responses are quite rare [3,4]. Combination chemotherapy has produced increases both in the response rate and percentage of complete responses [5]. In recent years a new agent, cis-diamminedichloroplatinum has shown high activity in ovarian cancer [6] and combination chemotherapy including CDDP has further raised the response rate to 70-90% [7-111. Furthermore the association of aggressive debulking surgery followed by platinum-based combination chemotherapy has substantially increased the percentage of surgically documented complete remissions. Some of these complete responders may be cured. Most of the published results have been obtained by combining CDDP with alkylating agents and/or Adriamycin. Unfortunately this combination is heavily myelosuppressive or car’ To whom correspondence should be addressed at: Clinica Ostetrica Ginecologica Universita, Viale Benedetto XV, 10, 16132, Genoa, Italy. 290 0090~8258/85 $1.50 Copyright All rights
0 1985 by Academic Press. Inc. of reproduction in any form reserved
POLICHEMOTHERAPY
IN
ADVANCED
OVARIAN
CANCER
291
diotoxic and not always feasible in elderly ovarian cancer patients who have already undergone aggressive surgery. In an attempt to reduce the toxicity and treat even older patients while maintaining efficacy, we have utilized a new combination chemotherapy regimen where moderate doses of CDDP are administered in two divided doses in association with two antimetabolites: methotrexate and S-fluorouracil. The two antimetabolites were chosen for their efficacy in monochemotherapy and their lack of leukemogenic activity. The aims of our study were (i) to assess the effectiveness of P, methotrexate (M), and 5-fluorouracil (F) in stage III-IV ovarian cancer patients following optimal debulking surgery (residual disease d 2 cm); (ii) to verify the feasibility of debulking surgery after six courses of PMF in those cases where, at diagnosis, optimal surgical resection had not been possible (residual disease > 2 cm, biopsy only); (iii) to evaluate the effectiveness and the toxicity of PMF in a consecutive series of patients with no age criteria exclusion. We present here our final results at 24 months follow-up. PATIENTS AND METHODS
The treatment plan was the following: after initial surgery, six PMF courses (P, 25 mg/m*, Days 1 and 8; M, 30 mg/m’, Day 1; F, 600 mg/m*, Day 1, iv, q 28) were administered. The patients who had an optimal debulking underwent a surgical second look after six courses of PMF. The patients with bulky residual disease (RD) after primary surgery (RD > 2 cm) underwent a second debulking procedure after six courses of PMF, if a clinical response had been achieved. Clinical response was evaluated by physical examination and serial echographies at 3-month intervals. After second surgery six further PMF courses were administered if a pathological complete response (PCR) was not documented. A few cases underwent a third-look surgery. The patients who progressed were submitted to second-line chemotherapy. Definition of response (clinical complete response, CCR; pathological complete response, PCR; clinical partial response, CPR; pathological partial response, PPR; and progression, P) was established according to ECOG criteria [12]. The eligibility criteria were histologically proven diagnosis of epithelial ovarian cancer FIG0 stage 111or IV; normal renal function; normal hemocytometry; no other malignancy. No age limit was set; the patients’ characteristics and surgical operation are summarized in Tables 1 and 2. Since June 1981, 38 consecutive patients entered the study: 10 relapsing patients pretreated with chemotherapy (4 with CDDP) and 28 untreated patients (of these 7 underwent optimal debulking surgery, RD s 2 cm; 19 suboptimal surgery with RD > 2 cm; 2 died after the first course of treatment due to extensive disease, and are considered for survival only, not for response). Survival time was measured in months from the first day of chemotherapy to the date of death or to time of last follow-up; survival time was analyzed using the life-table methods of Kaplan and Meier [13]. The statistical significance was tested by the log-rank test [14].
292
CONTE
ET AL.
TABLE 1 PATIENTS’
CHARACTERISTICS
38 38 36
Entered in study Evaluated for survival Evaluated for response Age Median Range Pretreatment Previously treated Untreated
52 37-84 10 28
AND PRIMARY SURGERY
Primary surgery” Complete surgery Incomplete surgery Biopsy only FIG0 stage” III IV Residual disease before CT” RD < 2 cm RD > 2 cm
15 1 12 19 9 8 20
’ Untreated patients only.
RESULTS In the 19 untreated patients with RD > 2 cm, a clinical response rate of 57.9% was observed (26.3% CCR, 31.6% CPR). In the 10 pretreated patients 4 CCR and 1 CPR were obtained (Table 3). Eighteen untreated patients (7 with RD G 2 cm, 11 with RD > 2 cm who experienced a CCR or CPR) underwent secondlook surgery. The following pathological responses were observed (Table 4): 5 PCR (3 patients with RD G 2 cm, 2 patients with RD > 2 cm) and 13 PPR (4 patients with RD G 2 cm, 9 patients RD > 2 cm). Of the 13 PPR, 3 showed microscopic disease; only 5 PPR patients could be further resected with resulting RD 6 2 cm. All the 13 PPR patients underwent six more cycles of PMF: 4 achieved a CCR and were submitted to third look, but pathological residual disease was still present. Among pretreated patients two-fourths CR were confirmed at second look; interestingly one of these patients had been previously pretreated with a CCDPcontaining regimen. The survival and the progression-free survival (PFS) for the entire group of patients and for the patients with more or less than 2 cm RD are reported in Figs. 1 and 2, respectively. The median survival for the entire group is 13.5 TABLE 2 TUMOR HISTOLOGY
Histology Serous Mutinous Endometrioid Undifferentiated Not specified G, G G Not specified y Untreated patients.
AND GRADINGS
No. patients 9 4 2 2 11 3 5 5 15
POLICHEMOTHERAPY
IN
ADVANCED
OVARIAN
293
CANCER
TABLE 3 CLINICAL RESFQNSEIN EVALUABLE PATIENTS’ AT 3 MONTHS
No. patients
OR%
CCR%
CPR%
P%
19
57.9 50.0
26.3 40.0
31.6 10.0
42.1 50.0
PCRW
PPRW
P%”
19.2 10.5 42.9 30.0
50.0 47.4 57.1 20.0
30.8 42. I 50.0
Untreated patients Pretreated patients
10
” Residual disease > 2 cm.
TABLE 4 SURGICAL RESFQNSEAT SECOND-LOOK SURGERY
No. secondlook surgery
No. patients Total untreated >2 cm RD ~2 cm RD Pretreated
18 11 7
26 19
7 10
2
’ Percentages refer to the initial number of patients (column 1).
.-._.-.-.- .-.-f \\
cweru,, PtS (581 residual
',L.-.-.-.-.-. __
((
disease cc
s 2Cm (9)
.-.-.~.-.-
> *cm (29)
------
\ \
;.---,
101
I--.----ntrtb~fron
the
is start
of
72lthe trcrtnlcnt
FIG. 1. Survival. Median survival for all patients is 13.5 months, median survival for patients with initial residual disease more than 2 cm is 10.5 months, median survival for patients with initial disease less than 2 cm has not yet been reached. The difference in survival between the two patients population is significant (P < 0.05).
294
CONTE ET AL.
over011 P’(S (381 reslduol disease s2cm (9) .-.-.-.-.z2cm (29) -----(( N
1
5
months
fa from
the
start
15 of the
20 treatment
25
FIG. 2. Progression-free survival. Median time to progression for all patients is 9 months, median time to progression for patients with initial residual disease more than 2 cm is 8.3 months, median time to progression for patients with initial residual disease less than 2 cm has not yet been reached at 24 months. The difference between the two patients population is significant (P < 0.025).
months (10.5 months for the patients with more than 2 cm RD; while it has not yet been reached at 24 months for the patients with less than 2 cm RD). At 24 months overall survival is 19.2% and probability of PFS 10.9% (66.6% for patients with RD 6 2 cm, 0% for the patients with RD greater than 2 cm). Survival and PFS according to the type of pathological response are reported in Figs. 3 and 4. For the seven patients who achieved a PCR the 2-year survival and PFS rates are 50 and 60%, respectively and are significantly better p < 0.00025) than those observed in nonresponders. No grade 2-3 ECOG renal or hemathological toxicity was recorded during the chemotherapeutic cycles. DISCUSSION Combination chemotherapy with platinum, alkylating agents, and/or Adriamycin is a highly effective induction regimen in advanced ovarian carcinoma and clinical complete remission rate of 60-80% can be achieved [7-l I]. However, these regimens often show gastrointestinal, renal, and bone marrow toxicities and many older patients cannot withstand these treatments [9,11]. Therefore we have tried to evaluate the efficacy of a more tolerable regimen, PMF. Our results confirm that a high response rate can be achieved: 57.9% OR in patients with clinically evaluable RD; 42.9% PCR in patients with optimally resected disease. Moreover, despite the inclusion of elderly patients in the study,
POLICHEMOTHERAPY
IN
ADVANCED
OVARIAN
10 _--15’. .8 ---;a--------__----_ i
\\.‘- -1
1,
901
13---\
\\
‘\\7\,.-. 12',
295
CANCER
PCR (8)
~
PPn 115)
------
P
(131
-.
'1
80
'> I,'---\ \
'\
9:,
7?
-5
.3
ki \
I
,
a0 \ ,l-.
\
-boo~~ ~~~~~~*~ of
the
treatment
3. Survival according to response. Actuarial survival at 24 months for complete responders is 50%. No progressor survived beyond 14 months. The difference in survival between responders (CR + PR) and nonresponders (P) is significant (P < 0.00025). FIG.
roogh 9
%T
-8 -__-_ch_- 15’ ‘\ i \I I**---* i :\
PCR (8)
~
PPR (15)
------
4
-5--
months
l-0
from
the
start
f5
of
the
20 treatment
25
4. Progression-free survival according to response. A significant difference is evident between responders (CR + PR) and nonresponders (P) (P < 0.00025) while no significant difference is detectable between CR vs PR (P < 0.25). FIG.
296
CONTE ET AL.
no grade 2 ECOG renal or myelotoxicity was observed. A 50% response rate has been obtained even in pretreated patients with two PCR documented at second look. The importance of second-look laparotomy to prove the type of response to chemotherapy is confirmed by our study. Fewer than 50% of the patients in CCR are free of disease at surgery. Achievement of a PCR is important for survival; about 60% of PCR patients will be disease free at 24 months. The probability of reaching a PCR is related to the extent of RD after initial surgery; 42.9% of patients with RD s 2 cm will obtain a PCR versus 10.5% of patients with bulky RD. Though the role of second-look surgery may be essential in the identification of those patients pathologically free of disease who can stop treatment, its therapeutic value still remains to be determined. In our series 13 patients were in PPR at second look; 3 patients had microscopic disease only, and 5 patients were further resected with resulting RD s 2 cm. All these patients were treated with further six PMF courses but no PCR was documented in the 4 patients who underwent a third-look laparotomy. In conclusion our results confirm that (i) ovarian cancer patients can be treated safely and effectively with combination chemotherapy including moderate doses of CDDP; (ii) achievement of a PCR depends on the extent of RD after initial surgery; (iii) patients who achieve a PCR have a longer survival; and (iv) secondlook surgery is essential for accurate evaluation of the extent of response to treatment, but its therapeutic value remains to be demonstrated. REFERENCES 1. Silverberg, E. Cancer statistics, Cancer 31, 13-28 (1981). 2. Aure, J. C., Hoeg, K., and Kolstad, P. Clinical and histological studies of ovarian carcinoma. Long term follow-up of 990 cases, Obstet. Gynecol. 37, l-9 (1977). 3. Smith, J. P., and Rutledge, F. Chemotherapy in the treatment of cancer of the ovary, Amer. J. Obstet. Gynecol. 107, 691-703 (1970). 4. Young, R. C. Chemotherapy of ovarian cancer: Past and present, Semin. Oncol. 2, 267-276 (1975). 5. Young, R. C., Chabner, B. A., Hubbard, S. P., Fisher, R. I., Bender, R. A., Anderson, T., Simon, R. M., Canellos, G. P., and De Vita, V. T. Advanced ovarian carcinoma. A prospective clinical trial of Melphalan (L-PAM) versus combination chemotherapy, N. Engl. J. Med. 299, 1261-1266 (1978). 6. Wiltshaw, E., and Can, B. Cis-plantinum (II) diammino-dichloride clinical experience of the Royal Marsden and Institute of Cancer Research, Recent Results Cancer Res. 48, 178-182 (1978). 7. Ehrlich, C. E., Einhorn, L., Williams, S. D., and Morgan, J. Chemotherapy for stage III-IV epithelial ovarian cancer with cis-dichlorodiammine-platinum (II), adriamycin and cyclophosphamide: A preliminary report, Cancer Treat. Rep. 63, 281-288 (1979). 8. Barker, G. H., and Wiltshaw, E. Randomized trial comparing low-dose cis-platin and chlorambucil with low-dose cisplatin, chlorambucil and doxorubicin in advanced ovarian carcinoma, Lancer 1, 747-750 (1981). 9. Cohen, C. J., Goldberg, J. D., Holland, J. F., Bruckner, H. W., Deppe, G., Gusberg, S. B., Wallach, R. C., Kabakow, B., and Rodin, J. Improved therapy with cisplatin regimens for patients with ovarian carcinoma (FIG0 stages III and IV) as measured by surgical end staging (second-look operation), Amer. J. Obstet. Gynecol. 145, 955-967 (1983).
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